New benzoquinolizin-5-one derivatives as furocoumarin analogs: DNA-interactions and molecular modeling studies

Three derivatives of 1H, 5H and 3H,SH-benzo[ij]quinolizin-5-one (BQZ(1)), p reviously prepared by chemical synthesis with the aim of obtaining furocoum arin analogs, have been studied. These are able to intercalate inside DNA a nd by subsequent irradiation with UVA light, to photoreact with DNA. Compou nd I (10-methoxy-7-methyl-1H, 5H-benzo[ij]quinolizin-5-one) has a potential ly photoreactive 2, 3 double bond because of its conjugation with the pyrid ine ring of quinolinone, while compounds II (10-acetoxy-7-methyl-3H, 5H-ben zo[ij]quinolizin-5-one) and III (10-methoxy-7-methyl-3H,SH-benzo[ij]quinoli zin-5-one) have a potentially photoreactive 1,2 double bond conjugated with the benzene ring of quinolinone. Compounds I and III, having a tricyclic p lanar structure, intercalate inside the DNA, while compound II cannot inter calate efficiently because of the steric hindrance of the acetoxy group in 10, lying outside the plane of the molecule and rotated by an angle of 77.6 degrees with respect to the tricyclic plane. The photoreaction of BQZ with DNA structure, as already known for psoralen and angelicin derivatives, co nsists of a [2 + 2] photocycloaddition reaction with the pyrimidine bases. The main photoadduct between the 2,3 double bond of I and the 5, 6 double b ond of thymine has been isolated and characterized by NMR, showing a cis-an ti structure. Theoretical calculations, using AMI Hamiltonian, have been ca rried out to describe the photocycloaddition reaction mechanism better. Fro m a theoretical point of view, in the case of BQZ both the 1,2 or 2,3 doubl e bonds and the 6, 7 double bond may be involved in the [2 + 2] photocycloa ddition. Spin densities and molecular orbital symmetries of compound I, in its triplet state, suggest that the 2,3 double bond interacts favorably wit h the 5,6 double bond of thymine moiety. On the contrary, the acetoxy subst ituent in position 10 of II seems to play a negative role in the DNA interc alation process. (C) 1999 Elsevier Science S.A. All rights reserved.